Novel aminoindanes

ABSTRACT

The present invention relates to therapeutically active novel aminoindanes of formula (I). Also provided is a method of preparing compounds of formula (I), and pharmaceutical compositions comprising the compounds. The novel compounds act as modulators of metabotropic glutamate receptors and, as such, are useful in treating diseases of the central nervous system related to the metabotropic glutamate receptor system.

FIELD OF THE INVENTION

[0001] This invention pertains to therapeutically active novelaminoindanes, a method for preparing the same, pharmaceuticalcompositions comprising the compounds and a method of treating diseasesof the Central Nervous System (CNS) therewith.

BACKGROUND OF THE INVENTION

[0002] The acidic amino acid L-glutamate is recognized as the majorexcitatory neurotransmitter in the CNS. The receptors that respond toL-glutamate are called excitatory amino acid receptors. The excitatoryamino acid receptors are thus of great physiological importance, playinga role in a variety of physiological processes, such as long-termpotentiation (learning and memory), the development of synapticplasticity, motor control, respiratory and cardiovascular regulation,and sensory perception.

[0003] Excitatory amino acid receptors are classified into two generaltypes and both are activated by L-glutamate and its analogs. Receptorsactivated by L-glutamate that are directly coupled to the opening ofcation channels in the cell membrane of the neurons are termed“ionotropic.” This type of receptor has been subdivided into at leastthree subtypes, which are defined by the depolarizing actions of theselective agonists N-Methyl-D-aspartate (NMDA),α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and Kainicacid (KA).

[0004] The second general type of receptor is the G-protein or secondmessenger-linked “metabotropic” excitatory amino acid receptor. Thissecond type is coupled to multiple second messenger systems that lead toenhanced phosphoinositide hydrolysis, activation of phospholipase D,increases or decreases in cAMP formation, and changes in ion channelfunction (Schoepp and Conn, Trends in Pharmacological Science, 14:13,1993). Both types of receptors appear not only to mediate normalsynaptic transmission along excitatory pathways but also to participatein the modification of synaptic connections during development andthroughout life.

[0005] So far eight different clones of the G-protein-coupled mGluRshave been identified (Knopfel et al., 1995, J. Med. Chem., 38,1417-1426). These receptors function to modulate the presynaptic releaseof L-glutamate, and the postsynaptic sensitivity of the neuronal cell toL-glutamate excitation. Based on pharmacology, sequence homology and thesignal transduction pathway that they activate, the mGluRs have beensubclassified into three groups. The mGluR₁ and mGluR₅ receptors formgroup I. They are coupled to hydrolysis of phosphatidylinositol (PI) andare selectively activated by (RS)-3,5-dihydroxyphenylglycine (Brabet etal., Neuropharmacology, 34, 895-903, 1995). Group II comprises mGluR₂and mGluR₃ receptors. They are negatively coupled to adenylate cyclaseand are selectively activated by(2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; Hayashi etal., Nature, 366, 687-690, 1993). Finally, the mGluR4, mGluR6, mGluR₇and mGluR₈ receptors belong to group III. They are also negativelycoupled to adenylate cyclase and are selectively activated by(L)-2-amino-4-phosphonobutyric acid (L-AP4; Knopfel et al., 1995, J. MedChem., 38, 1417-1426).

[0006] Agonists and antagonists of these receptors are believed usefulfor the treatment of acute and chronic neurodegenerative conditions, andas antipsychotic, anticonvulsant, analgesic, anxiolytic, antidepressant,and anti-emetic agents. Antagonists and agonists of neural receptors areclassified as selective for a particular receptor or receptor subtype,or as non-selective. Antagonists may also be classified as competitiveor non-competitive. While competitive and non-competitive antagonistsact on the receptors in a different manner to produce similar results,selectivity is based upon the observations that some antagonists exhibithigh levels of activity at a single receptor type, and little or noactivity at other receptors. In the case of receptor-specific diseasesand conditions, the selective agonists and antagonists are of the mostvalue.

[0007] Compounds such as L-Glutamic acid, Quisqualic acid and Ibotenicacid are known to act as non-selective agonists on the mGluRs, whileselective ionotropic glutamate receptor agonists such as NMDA, AMPA andkainate have little effect on these receptors. Recently a few compoundswithout activity at the ionotropic glutamate receptors but with activityat the metabotropic receptors have been identified. These includetrans-ACPD (trans-(1S,3R)-1-aminocyclopentane-1,3-dicarbokylic acid),the partial agonist L-AP3 (L-2-amino-3-phosphonopropionic acid; Palmer,E., Monaghan, D. T. and Cotman, C. W. Eur. J. Pharmacol. 166, 585-587,1989; Desai, M. A. and Conn, P. J. Neuroscience Lett. 109, 157-162,1990; Schoepp, D. D. et al., J. Neurochemistry. 56, 1789-1796, 1991;Schoepp D. D. and Johnson B. G. J. Neurochemistry 53, 1865-1913, 1989),L-AP4 (L-2-amino-4-phosphonobutyric acid) which is an agonist at themGluR₄ receptor (Thomsen C. et al., Eur. J. Pharmacol. 227, 361-362,1992) and some of the isomers of CCG (2-(carboxycyclopropyl)glycines)especially L-CCG-I and L-CCG-II (Hayashi, Y. et al., Br. J. Pharmacol.107, 539-543, 1992).

[0008] Very few selective antagonists at the mGluRs have been reported.However some phenylglycine derivatives, S-4CPG(S-4-carboxyphenylglycine), S-4C3HPG (S4-carboxy-3-hydroxyphenylglycine)and S-MCPG (S-α-methyl-4-carboxyphenylglycine) have been reported toantagonize trans-ACPD- stimulated phosphoinositide hydrolysis and thuspossibly act as antagonists at mGluR, and mGluR₅ subtypes (Thomsen, C.and Suzdak, P, Eur. J. Pharmacol. 245, 299, 1993).

[0009] Research directed towards mGluRs is beginning to show that mGluRsmay be implicated in a number of normal as well as pathologicalmechanisms in the brain and spinal cord. For example, activation ofthese receptors on neurons can: influence levels of alertness, attentionand cognition; protect nerve cells from excitotoxic damage resultingfrom ischemia, hypoglycemia and anoxia; modulate the level of neuronalexcitation; influence central mechanisms involved in controllingmovement; reduce sensitivity to pain; reduce levels of anxiety.

[0010] The use of compounds active at the mGluRs for the treatment ofepilepsy is corroborated by investigations of the influence oftrans-ACPD on the formation of convulsions (Sacaan and Schoepp,Neuroscience Lett. 139, 77, 1992) and that phosphoinositide hydrolysismediated via mGluR is increased after kindling experiments in rats(Akiyama et al. Brain Res. 569, 71, 1992). Trans-ACPD has been shown toincrease release of dopamine in the rat brain, which indicates thatcompounds acting on the mGluRs might be usable for the treatment ofParkinson's disease and Huntington's Chorea (Sacaan et al., J.Neurochemistry 59, 245, 1992).

[0011] Trans-ACPD has also been shown to be a neuroprotective agent in amedial cerebral artery occlusion (MCAO) model in mice (Chiamulera et al.Eur. J. Pharmacol. 215, 353, 1992), and it has been shown to inhibitNMDA-induced neurotoxicity in nerve cell cultures (Koh v, Proc. Natl.Acad Sci. USA 88, 9431, 1991). The mGluR-active compounds are alsoimplicated in the treatment of pain. This is proved by the fact thatantagonists at the mGluRs antagonize sensory synaptic response tonoxious stimuli of thalamic neurons (Eaton, S. A. et al., Eur. JNeuroscience, 5, 186, 1993).

[0012] The use of compounds active at the mGluRs for treatment ofneurological diseases such as senile dementia have also been indicatedby the findings of Zheng and Gallagher, Neuron 9, 163, 1992 and Bashiret al. (Nature 363, 347, 1993) who demonstrated that activation ofmGluRs is necessary for the induction of long-term potentiation (LTP) innerve cells (septal nucleus, hippocampus) and the finding that long-termdepression is induced after activation of mGluRs in cerebellar granulecells (Linden et al. Neuron 7, 81, 1991).

[0013] Thus compounds that demonstrate either activating or inhibitingactivity at mGluRs have therapeutic potential for the treatment ofneurological disorders. These compounds have application as new drugs totreat both acute and chronic neurological disorders, such as stroke andhead injuries; epilepsy; movement disorders associated with Parkinson'sdisease and Huntington's chorea; pain; anxiety; AIDS dementia; andAlzheimer's disease. Since the mGluRs can influence levels of alertness,attention and cognition; protect nerve cells from excitotoxic damageresulting from ischeria, hypoglycemia and anoxia; modulate the level ofneuronal excitation; influence central mechanisms involved incontrolling movement; reduce sensitivity to pain; and reduce levels ofanxiety, these compounds can also be used to influence these situationsand also find use in learning and memory deficiencies such as seniledementia. mGluRs may also be involved in addictive behaviour,alcoholism, drug addiction, sensitization and drug withdrawal (Science,280:2045, 1998), so compounds acting at mGluRs might also be used totreat these disorders.

[0014] The current pharmaceutical options for treating neurologicaldisorders tend to be very general and non-specific in their actions inthat, although they may reduce the clinical symptoms associated with aspecific neurological disorder, they may also negatively impact normalfunction of the central nervous system of patients. Thus new cellulartargets and drugs that are more specific in their actions require to beidentified and developed and thus a need remains for chemical compoundsthat demonstrate specific binding characteristics towards mGiuRs.

BRIEF DESCRIPTION OF THE FIGURES

[0015]FIG. 1 demonstrates the actions of compounds of the presentinvention as antagonists of phosphatidyl inositol hydrolysis evokedthrough the mGluR1 receptor by 10 μM (L)-glutaminc acid. (650201corresponds to compound 4b and 650202 corresponds to compound 4a)

SUMMARY OF THE INVENTION

[0016] An object of the present invention is to provide novelaminoindanes that demonstrate activity at the various metabotropicglutamate receptors. In accordance with an aspect of the invention,there is provided a compound of formula (I):

[0017] stereoisomers thereof, or pharmaceutically acceptable salts orhydrates thereof, wherein:

[0018] R1, and R2 are selected from the group comprising:

[0019] 1) H; or.

[0020] 2) an acidic group selected from the group comprising carboxy,phosphono, phosphino, sulfono, sulfono, borono, tetrazol, isoxazol,—(CH₂)_(n)-carboxy, —(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino,—(CH₂)_(n)-sulfono,—(CH₂)_(n)-sulfono, —(CH₂)_(n)borono,—(CH₂)_(n)-tetrazol, and —(CH₂)_(n)-isoxazol, where n =1, 2, 3, 4, 5, or6; or:

[0021] X is an acidic group selected from the group comprising carboxy,phosphono, phosphino, sulfono, sulfono, borono, tetrazol, isoxazol;

[0022] Y is a basic group selected from the group comprising 1° amino,2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino,aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammoniumsalts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromaticquaternary ammonium salts, imidazol, guanidino, boronoamino, allyl,urea, thiourea;

[0023] m is 0, 1; and

[0024] R3, R4, R5, R6 are independently H, nitro, amino, halogen,tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl,sulfamoyl or pharmaceutically acceptable esters or salts thereof

DETAILED DESCRIPTION OF THE INVENTION

[0025] The terms and abbreviations used in the instant examples havetheir normal meanings unless otherwise designated. For example “° C.”refers to degrees Celsius; “N” refers to normal or normality; “mmol”refers to millimole or millimoles; “g” refers to gram or grams; “ml”means milliliter or milliliters; “M” refers to molar or molarity; “p-”refers to para, “MS” refers to mass spectrometry; “IR” refers toinfrared spectroscopy; and “NMR” refers to nuclear magnetic resonancespectroscopy.

[0026] As would be understood by the skilled artisan, throughout thesynthesis of the compounds of Formula I it may be necessary to employ anamino-protecting group or a carboxy-protecting group in order toreversibly preserve a reactively susceptible amino or carboxyfunctionality while reacting other functional groups on the compound.

[0027] Examples of such amino-protecting groups include formyl, trityl,phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, andurethane-type blocking groups such as benzyloxycarbonyl,4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl,2-(4-xenyl)-isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxy-carbonyl,1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxycarbonyl(“FMOC”), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decycloxy)benzyloxycarbonyl,isobornyloxycarbonyl, 1-piperidyloxycarbonlyl and the like;benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphineoxide and like amino-protecting groups. The species of amino-protectinggroup employed is not critical so long as the derivatized amino group isstable to the condition of subsequent reaction(s) on other positions ofthe intermediate molecule and can be selectively removed at theappropriate point without disrupting the remainder of the moleculeincluding any other amino-protecting group(s). Preferredarino-protecting groups are t-butoxycarbonyl (t-Boc), allyloxycarbonyland benzyloxycarbonyl (CbZ). Further examples of these groups are foundin E. Haslarm, Protecting Groups in Organic Chemistry, (J. G. W. McOmie,ed., 1973), at Chapter 2; and T. W. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, (1991), at Chapter 7.

[0028] Examples of such carboxy-protecting groups include methyl,p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl,pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl,4,4′-dimethoxybenzhydryl, 2,2′,4,4′-tetramethoxybenzhydryl, t-butyl,t-amyl, trityl, 4-methoxytrityl, 4,4′-dimethoxytrityl,4,4′,4″-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl,t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl,4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. Preferredcarboxy-protecting groups are allyl, benzyl and t-butyl. Furtherexamples of these groups are found in E. Haslam, supra, at Chapter 5;and T. W. Greene and P. G. M. Wuts, supra, at Chapter 5.

[0029] The present invention provides a compound of the formula I:

[0030] Stereoisomers thereof, or pharmaceutically acceptable salts orhydrates thereof, wherein:

[0031] R1, and R2 are selected from the group comprising:

[0032] 1) H

[0033] 2) an acidic group selected from the group comprising carboxy,phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol,—(CH₂)_(n)-carboxy, —(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino,—(CH₂)_(n)-sulfono,—(CH₂)_(n)-sulfino, —(CH₂)_(n)borono,—(CH₂)_(n)tetrazol, and —(CH₂)_(n)-isoxazol, where n 1, 2, 3, 4, 5, or6; or

[0034] X is an acidic group selected from the group comprising carboxy,phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol;

[0035] Y is be a basic group selected from the group comprising 1°amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1°amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternaryammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino,aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino,allyl, urea, thiourea;

[0036] m can be 0, 1; and

[0037] R3, R4, R5, R6 are independently H, nitro, amino, halogen,tritium, trifluoromethyl, trifluoroacetyl sulfo, carboxy, carbamoyl,sulfamoyl or pharmaceutically acceptable esters or salts thereof

[0038] In one embodiment of the present invention a compound of formula(I) is provided, wherein: R1 is CO₂H, or CH₂CO₂H; R2 is H; X is CO₂H;and Y is NH₂

[0039] In another embodiment of the present invention a compound offormula (I) is provided, wherein:

[0040] R1 is H; R2 is CO₂H or CH₂CO₂H; X is CO₂H; and Y is NH₂.

[0041] Compounds of the present invention include, but are not limitedto the following exemplary molecules:

[0042] While all of the compounds of Formula I are believed todemonstrate activity at the metabotropic glutamate receptors (mGluRs),certain groups of Formula I compounds are more preferred for such use.

[0043] As noted supra, this invention includes the pharmaceuticallyacceptable salts of the compounds defined by Formula I. A compound ofthis invention can possess a sufficiently acidic, a sufficiently basic,or both functional groups, and accordingly react with any of a number oforganic and inorganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt.

[0044] The term “pharmaceutically acceptable salt” as used herein,refers to salts of the compounds of the above formula which aresubstantially non-toxic to living organisms. Typical pharmaceuticallyacceptable salts include those salts prepared by reaction of thecompounds of the present invention with a pharmaceutically acceptablemineral or organic acid or an organic or inorganic base. Such salts areknown as acid addition and base addition salts.

[0045] Acids commonly employed to form acid addition salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydriodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, rilonohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,napththalene-2-sulfonate, mandelate and the like.

[0046] Preferred pharmaceutically acceptable acid addition salts arethose formed with mineral acids such as hydrochloric acid andhydrobromic acid, and those formed with organic acids such as maleicacid and methanesulfonic acid.

[0047] Salts of amine groups may also comprise quarternary aminoniumsalts wherein the amino nitrogen carries a suitable organic group suchas an alkyl, alkenyl, alkynyl, or aralkyl moiety.

[0048] Base addition salts include those derived from inorganic bases,such as ammonium or alkali or alkaline earth metal hydroxides,carbonates, bicarbonates, and the like. Such bases useful in preparingthe salts of this invention thus include sodium hydroxide, potassiumhydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate,sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

[0049] It should be recognized that the particular counterion forming apart of any salt of this invention is usually not of a critical nature,as long as the salt as a whole is pharmacologically acceptable and aslong as the counterion does not contribute undesired qualities to thesalt as a whole.

[0050] This invention further encompasses the pharmaceuticallyacceptable solvates of the compounds of Formula I. Many of the Formula Icompounds can combine with solvents such as water, methanol, ethanol andacetonitrile to form pharmaceutically acceptable solvates such as thecorresponding hydrate, methanolate, ethanolate and acetonitrilate.

[0051] The compounds of the present invention have multiple asymmetric(chiral) centers. As a consequence of these chiral centers, thecompounds of the present invention occur as racemates, mixtures ofenantiomers and as individual enantiomers, as well as diastereomers andmixtures of diastereomers. All asymmetric forms, individual isomers andcombinations thereof, are within the scope of the present invention.

[0052] The prefixes “R” and “S” are used herein as commonly used inorganic chemistry to denote the absolute configuration of a chiralcenter, according to the Cahn-Ingold-Prelog system. The stereochemicaldescriptor R (rectus) refers to that configuration of a chiral centerwith a clockwise relationship of groups tracing the path from highest tosecond-lowest priorities when viewed from the side opposite to that ofthe lowest priority group. The stereochemical descriptor S (sinister)refers to that configuration of a chiral center with a counterclockwiserelationship of groups tracing the path from highest to second-lowestpriority when viewed from the side opposite to the lowest prioritygroup. The priority of groups is decided using sequence rules asdescribed by Cahn et al., Angew. Chem., 78, 413-447, 1966 and Prelog, V.and Helmchen, G.; Angew. Chem. Int. Ecd Eng., 21, 567-583, 1982).

[0053] In addition to the R,S system used to designate the absoluteconfiguration of a chiral center, the older D-L system is also used inthis document to denote relative configuration, especially withreference to amino acids and amino acid derivatives. In this system aFischer projection of the compound is oriented so that carbon-1 of theparent chain is at the top. The prefix “D” is used to represent therelative configuration of the isomer in which the functional(determining) group is on the right side of the carbon atom at thechiral center and “L”, that of the isomer in which it is on the left.

[0054] As would be expected, the stereochemistry of the Formula Icompounds is critical to their potency as agonists or antagonists. Therelative stereochemistry is preferably established early duringsynthesis, which avoids stereoisomer separation problems later in theprocess. Subsequent synthetic steps then employ stereospecificprocedures so as to maintain the preferred configuration. The preferredmethods of this invention are the methods employing those preferredcompounds.

[0055] Non-toxic metabolically labile esters and amides of compounds ofFormula I are ester or amide derivatives of compounds of Formula I thatare hydrolyzed in vivo to afford said compounds of Formula I and apharmaceutically acceptable alcohol or amine. Examples of metabolicallylabile esters include esters formed with (C₁-C₆) alkanols in which thealkanol moiety may be optionally substituted by a (C₁-C₈) alkoxy group,for example methanol, ethanol, propanol and methoxyethanol. Examples ofmetabolically labile amides include amides formed with amines such asmethylamine.

[0056] Preparation of Compounds of Formula (1)

[0057] According to another aspect, the present invention provides aprocess for the preparation of a compound of Formula I, or apharmaceutically acceptable metabolically-labile ester or amide thereof,or a pharmaceutically acceptable salt thereof, which comprises:

[0058] (a) hydrolyzing a compound of formula (IIa) or (IIb)

[0059] wherein:

[0060] R1, R2, R3, R4, R5 and R6 are as defined above. R7 is a hydrogenatom or an acyl group. Preferred functional groups for R7 are hydrogenand (C₂-C₆) alkanoyl groups, such as acetyl; or

[0061] (b) hydrolyzing a compound of formula (IIIa) or (IIIb):

[0062] wherein:

[0063] R1, R2, R3, R4, R5 and R6 are as defined above, R8 and R9 areeach independently represent a hydrogen atom, a (C₂-C₆) alkanoyl group,a (C₁-C₄) alkyl group, a (C₃-C₄) alkenyl group or a phenyl (C₁-C₄) alkylgroup, wherein the phenyl is unsubstituted or substituted by halogen,(C₁-C₄) alkyl or (C₁-C₄) alkoxy, or a salt thereof, or

[0064] (c) deprotecting a compound of formula (IVa) or (IVb):

[0065] wherein:

[0066] R1, R2, R3, R4, R5 and R6 are as defined above and R10 is ahydrogen atom or a carboxyl protecting group, or a salt thereof, and R11is a hydrogen atom or a nitrogen protecting group;

[0067] whereafter, if necessary and/or desired, the following steps arecarried out:

[0068] (i) resolving the compound of Formula I;

[0069] (ii) converting the compound of Formula I into a non-toxicmetabolically labile ester or amide thereof, and/or;

[0070] (iii) converting the compound of Formula I or a non-toxicmetabolically labile ester or amide thereof into a pharmaceuticallyacceptable salt thereof.

[0071] Compounds of formulae (II), (III) and (IV), wherein at least oneof R3, R4, R5 and R6 is other than H may be prepared from the compoundsof formula (II), (III) and (IV) respectively, wherein: R3, R4, R5 and R6is H, using standard reactions known to a person skilled in the art. Forexample: electrophilic substitution with appropriate electrophile,Friedel-Crafts alkylation or acylation, followed by furthermanipulations of the formed products within the knowledge of a workerskilled in the art.

[0072] The protection of carboxylic acid and amine groups is generallydescribed in McOmie, Protecting Groups in Organic Chemistry, PlenumPress, N.Y., 1973, and Greene and Wuts, Protective Groups in OrganicSynthesis, 2nd. Ed., John Wiley & Sons, NY, 1991. Examples of carboxyprotecting groups include alkyl groups such as methyl, ethyl, t-butyland t-amyl; aralkyl groups such as benzyl, 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, benzhydryl and trityl;silyl groups such as trimethylsilyl and t-butyldimethylsilyl; and allylgroups such as allyl and 1-(trimethylsilylmethyl)prop-1-en-3-yl.Examples of amine protecting groups include acyl groups, such as groupsof formula —C(O)R11 in which R11 represents (C₁-C₆) alkyl, (3-10C)cycloalkyl, phenyl (C₁-C₆) alkyl, phenyl (C₁-C₆) alkoxy, or a (C₃-C₁₀)cycloalkoxy, wherein a phenyl group may optionally be substituted by oneor two substituents independently selected from amino, hydroxy, nitro,halogeno, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, carboxy, (C₁-C₆)alkoxycarbonyl, carbamoyl, (C₁-C₆) alkanoylamino, (C₁-C₆)alkylsulphonylamino, phenylsulphonylamino, toluenesulphonylamino, and(C₁-C₆) fluoroalkyl.

[0073] The compounds of Formula II are conveniently hydrolyzed in thepresence of an acid, such as hydrochloric acid or sulfuric acid, or abase, such as an alkali metal hydroxide, for example sodium hydroxide.The hydrolysis is conveniently performed in an aqueous solvent such aswater and at a temperature in the range from 50 to 200 ° C.

[0074] The compounds of Formula III are conveniently hydrolyzed in thepresence of a base, for example an alkali metal hydroxide such aslithium, sodium or potassium hydroxide, or an alkaline earth metalhydroxide such as barium hydroxide. Suitable reaction media includewater. The temperature is conveniently in the range from 50 to 150 ° C.

[0075] The compounds of Formula IV may be deprotected by conventionalmethods. Thus, an alkyl carboxyl protecting group may be removed byhydrolysis. The hydrolysis may conveniently be performed by heating thecompound of Formula IV in the presence of either a base, for example analkali metal hydroxide such as lithium, sodium or potassium hydroxide,or an alkaline metal hydroxide, such as barium hydroxide, or an acidsuch as hydrochloric acid. The hydrolysis is conveniently performed at atemperature in the range from 10 ° to 300 ° C. An aralkylcarboxyl-protecting group may conveniently be removed by hydrogenolysis.The hydrogenolysis may conveniently be effected by reacting the compoundof Formula IV with hydrogen in the presence of a Group VIII metalcatalyst, for example a palladium catalyst such as palladium oncharcoal. Suitable solvents for the reaction include alcohols such asethanol. The reaction is conveniently performed at a temperature in therange from 0 ° to 100 ° C. An acyl amine protecting group is alsoconveniently removed by hydrolysis, for example as described for theremoval of an alkyl carboxyl protecting group.

[0076] The compounds of Formula (IIa) and (IIb) may be prepared byreacting compounds of formula (Va) and (Vb) respectively:

[0077] wherein: R1, R2, R3, R4, R5 and R6 are as defined above; with analkali metal cyanide, such as lithium, sodium or potassium cyanide, andeither ammonium carbonate in an aqueous alcohol, such as aqueous ethanolor with an ammonium halide, such as ammonium chloride, conveniently inthe presence of ultrasound. If the reaction is conducted with ammoniumcarbonate, the reaction is conveniently performed at a temperature inthe range from 35° C. to 150° C. If desired, the compounds of Formula IImay then be alkylated, for example using a compound of formula RCl,wherein: R is (C₁-C₆) straight or branched chain alkyl, or (C₁-C₆)alkanoyl group. As described in more detail hereinafter, the alkylatedcompounds may be readily separated into their diastereomers. If thereaction is conducted with an ammonium halide in the presence ofultrasound, the ammonium halide is mixed with chromatography gradealumina in the presence of a suitable diluent such as acetonitrile. Themixture is then irradiated with ultrasound, whereafter the compound ofFormula V is added, and the mitre is again irradiated. The alkali metalcyanide is then added, followed by further irradiation with ultrasound.

[0078] Individual isomers of compounds of Formula (IIa) and (IIb) may bemade by reacting a compound of the Formula V with the stereoisomers ofthe chiral agent (S)- and (R)-phenylglycinol and a reactive cyanide suchas trimethylsilyl cyanide to form the intermediate compounds of Formula(VIa) or (VIb), that can be further hydrolysed to give the desiredproducts.

[0079] The compounds of Formula III may be prepared by reacting acompound of Formula V with an alkali metal cyanide, such as lithium,sodium or potassium cyanide, and ammonium carbonate or ammoniumcarbamate. Common solvents include alcohols, such as methanol, aqueousmethanol and aqueous ethanol. Conveniently the reaction is performed ata temperature in the range of from 10° to 150° C. If desired, thecompounds of Formula m may then be alkylated, for example using anappropriate alky, aryl or acyl chloride.

[0080] The compounds of Formula (Va) are either commercially availableor may be prepared using standard procedures known to a person skilledin the relevant art. For example: compounds of formula (Va) can beprepared by reacting a compound of Formula VII with thionyl chloride orphosphorus pentachloride, and subjecting the resulting compound to theFriedel-Crafts acylation conditions.

[0081] wherein: R12 and R13 are together or independently CO₂H orCH₂CO₂H

[0082] In an alternative manner the compounds of formula (Va) can beprepared from compound VIII, by alkylation, followed by hydrolysis ofthe resulting compounds.

[0083] Compounds of formulae (VII), and (VII) are either commerciallyavailable or may be prepared using standard procedures known to a personskilled in the art. Compounds of formulae (VII), and (VII) wherein atleast one of R3, R4, R5 and R6 is other than H may be prepared from thecompounds of formulae (VII), and (VII) respectively, wherein R3, R4, R5and R6 is H, via standard reactions known to a person skilled in theart. For example: electrophilic substitution with appropriateelectrophile, Friedel-Crafts alkylation or acylation, followed byfurther. manipulations of the formed products within the knowledge of aworker skilled in the art.

[0084] The compounds of formula (Vb) may be prepared by reacting acompound of formula (Va) with Wittig salt such as (alkoxymethyl)triphenylphosphonium halide in the presence of alkali metal saltof bis (trimethylsilyl) amine or by reacting a compound of formula (Va)with Wittig reagent such as Ph₃P═CHOCH₃, followed by reaction withtrimethylsilyl halide.

[0085] Compounds of formulae (Va), and (Vb), wherein at least one of R3,R4, R5 and R6 is other than H may be prepared from the compounds offormula (Va) and (Vb) respectively, wherein R3, R4, R5 and R6 is H,using standard reactions known to a person skilled in the art. Forexample: electrophilic substitution with appropriate electrophile,Friedel-Crafts alkylation or acylation, followed by furthermanipulations of the formed products within the knowledge of a workerskilled in the art.

[0086] In an alternative manner, compounds of formula (V) may beprepared as taught in U.S. Pat. Nos.: 5,329,049; and 5,360,936.

[0087] Many of the intermediates described herein, for example thecompounds of Formula II, III and IV are believed to be novel, and areprovided as further aspects of the invention.

[0088] Biological and Therapeutic Activity of Compounds of Formula (I)

[0089] The compounds of formula I of the present invention exhibitagonists or antagonists activity toward certain metabotropic glutamatereceptors (mGluRs). Therefore, another aspect of the present inventionprovides a method of modulating the activity of mGluRs in mammals, whichcomprises administering to a mammal requiring modulated excitatory aminoacid neurotransmission a pharmacologically-effective amount of acompound of Formula I. The term “pharmacologically-effective amount” isused to represent an amount of the compound of the present inventionthat is capable of affecting the mGluRs. By modulating mGluR activity, acompound of the present invention is acting as an agonist or antagonistof mGluR. When a compound of the present invention acts as an agonist,the interaction of the compound with the excitatory amino acid receptormimics the response of the interaction of this receptor with its naturalligand, (i.e. L-Glutamic acid). When a compound of the invention acts asan antagonist, the interaction of the compound with the excitatory aminoacid receptor blocks or attenuates the response of the interaction ofthis receptor with its natural ligand, (i.e. L-Glutamic acid).

[0090] The particular dose of compound administered according to thepresent invention will, of course, be determined by the particularcircumstances surrounding the case, including the compound administered,the route of administration, the particular condition being treated, andsimilar considerations. The compounds can be administered by a varietyof routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, or intranasal routes. Alternatively, thecompound may be administered by continuous infusion. A typical dailydose will contain from about 0.001 mg/kg to about 100 mg/kg of theactive compound of this invention. Preferably, daily doses will be about0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg toabout 20 mg/kg. A variety of physiological functions have been shown tobe subject to influence by excessive or inappropriate stimulation ofexcitatory amino acid transmission. The Formula I compounds of thepresent invention are believed (through their interactions at themGluRs) to have the ability to treat a variety of neurological disordersin a warm-blooded mammals associated with abnormal excitatory amino acidtransmission, including but not limited to acute neurological disorderssuch as cerebral deficits subsequent to cardiac bypass surgery andgrafting, cerebral ischemia (e.g. stroke and cardiac arrest), spinalcord trauma, head trauma, perinatal hypoxia, and hypoglycemic neuronaldamage. Similarly, the Formula I compounds of the present invention,through their modulation of mGluR activity are believed to have theability to treat a variety of chronic neurological disorders, such asAlzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis,AIDS-induced dementia, ocular damage and retinopathy, cognitivedisorders, and idiopathic and drug-induced Parkinson's disease. Thepresent invention also provides methods for treating these disorderswhich comprises administering to a patient in need thereof an effectiveamount of a compound of Formula I.

[0091] The Formula I compounds of the present invention, through theirmodulation of mGluR activity are also believed to have the ability totreat a variety of other neurological disorders in mammals that areassociated with glutamate dysfunction, including muscular spasms,convulsions, migraine headaches, urinary incontinence, psychosis, drugtolerance, withdrawal, and cessation (i.e. opiates, benzodiazepines,nicotine, cocaine, or ethanol), smoking cessation, anxiety and relateddisorders (e.g. panic attack), emesis, brain edema, chronic pain, sleepdisorders, Tourette's syndrome, attention deficit disorder, and tardivedyskinesia. Therefore, the present invention also provides methods fortreating these disorders which comprise administering to a patient inneed thereof an effective amount of the compound of Formula I.

[0092] The Formula I compounds of the present invention, through theirmodulation of mGluR activity are also believed to have the ability totreat a variety of psychiatric disorders, such as schizophrenia, anxietyand related disorders (e.g. panic attack), depression, bipolardisorders, psychosis, and obsessive compulsive disorders. The presentinvention also provides methods for treating these disorders whichcomprises administering to a patient in need thereof an effective amountof a compound of Formula I.

[0093] Functional Assays Employing Cloned Subtypes of MetabotropicReceptors

[0094] The pharmacological properties of the compounds of the presentinvention can be determined via appropriate functional assays usingrecombinant metabotropic glutamate receptors. For example adenylatecyclase assays or phosphatidylinositol hydrolysis assays, performedusing standard procedures, can be used to determine agonist orantagonist activity towards mGluRs.

[0095] In Vitro Testing.

[0096] General in vifro assay methods include monitoring of adenylatecyclase activity and phosphatidyl inositol hydrolysis in a cell linethat expresses the appropriate mGluR.

[0097] (a) Adenylate Cyclase Activity

[0098] Adenylate cyclase activity is determined in initial experimentsin transfected mammalian cells, using standard techniques. See, e.g., N.Adharn, et al., Supra; R L. Weinshank, et al. Proc. Natl. Acad. Sci.(USA), 89:3630-3634 (1992), and the references cited therein.

[0099] Mammalian cells (the cell line AV12-664 is especially preferred)are stably transfected with a plasmid comprising the cloned metabotropicglutmate receptor. The cells are maintained in aa appropriate medium,for example one consisting of Dulbecco's Modified Eagle's Medium (DMEM)containing 5% dialyzed fetal calf serum, 10 mM HEPES buffer (pH 7.3), 1MM sodium pyruvate, 1 mM glutamine, and 200 μg/mL hygromycin.

[0100] For the assay the cells are disassociated from stock cultureflasks with trypsin, and plated in 24-well plastic tissue culture dishes(15 mm wells) at a density of 500,000-700,000 cells per well using thesame culture medium. After a twenty four hour incubation in a humidifiedCO₂ incubator, the cell monolayers are washed with buffer (for exampleDulbecco's phosphate-buffered saline containing 0.5 mM IBM and 3 mMglucose) and then incubated in the same buffer at 37° C. for 30 minutes.The monolayers are then washed with six exchanges of buffer.

[0101] Test compound(s) and forskolin, or forskolin alone, dissolved inbuffer, are added after the final wash. After incubating for 20 minutesat 37° C., 0.5 mL of 8 mM EDTA is added to each well. The plates arethen placed in a boiling water bath for about four minutes. Thesupematant fluids are recovered from the wells and lyophilized. CyclicAMP (cAMP) determinations are carried out on the lyophilized samplesusing commercially available radioimmunoassay kits, following themanufacturer's instructions. The cAMP levels in wells containing testcompound(s) are then compared to the forskolin controls.

[0102] (b) Phosphatidylinositol Assay

[0103] Phosphatidylinositol hydrolysis is measured in clonal cell lines(for example AV12) harbouring a plasmid expressing the clonedmetabotropic glutamate receptor in response to addition of glutamateagonists, as a functional assay for metabotropic glutamate receptoractivity according to D. Schoepp, Trends in Pharmaceutical Sciences,11:508, 1990.

[0104] Twenty four well tissue culture vessels are seeded withapproximately 250,000 cells per well in an appropriate medium forexample Dulbecco's Minimal Essential Media (D-MEM) (in the absence ofglutamic acid) containing 2 mM glutamine and 10% dialyzed fetal calfserum. After 24 hours growth at 37° C., the media is removed andreplaced with fresh media containing four microcuries of [³H]myoinositol per well and the cultures are incubated a further 16 to 20hours. The media is then removed and the cells in each well are washedwith serum free medium containing 10 mM lithium chloride, 10 mMmyoinositol, and 10 mM HEPES (2×1 mL washes). After the final wash, 0.5mL of washing solution is added containing the appropriateconcentration(s) of test compound(s).

[0105] If the particular assay is also testing antagonists, a tenminutes incubation is performed prior to antagonist induction. Cells areincubated for about one hour at 37° C. in 95%:5% O₂: CO₂ or asappropriate for time course. The reactions are terminated by removingmedia and adding 1 mL of cooled 1:1 acetone:methanol followed byincubation on ice for a minimum of twenty minutes.

[0106] These extracts are then collected and placed in 1.5 mL centrifugetubes. Each well is washed with 0.5 mL water and this wash is added tothe appropriate extract. After mixing and centrifugation, each aqueoussupernatant is processed by chromatography on a QMA SEP-PAK® column,which is prewetted and equilibrated by passing 10 mL of water, followedby 8 mL of 1M triethylammonium hydrogen carbonate (TEAB), followed by 10mL of water through the column.

[0107] The assay supernatants. containing the water soluble [³H]inositolphosphate are passed over the columns. This is followed by a 10 mL waterwash and a 4 mL wash with 0.02 M TEAB to remove [³H]inositol precursors.[³Cinositol phosphate is eluted with 4 mL of 0.1 M TEAB intoscintillation vials and counted in the presence of scintillationcocktail. Total protein in each sample is measured using standardtechniques. Measurements are taken as the amount of [³H]inositolphosphate released per milligram of protein.

[0108] The assays are carried out in the absence and in the presence ofthe compound being tested. The measurements of [³H]inositol phosphateper milligram of protein are compared in order to confirm agonist andantagonist activity of the compound being tested.

[0109] These types of assays, employing cell lines expressing differentsubtype of cloned metabotropic receptors, may be used to determine whichcompounds have selective affinity in that they modulate one subtype ofreceptor with a greater activity than another subtype.

[0110] (c) Testing in Chinese Hamster Cell Lines

[0111] The Chinese hamster ovary cell lines expressing mGluR_(1α), mGluR₂ and mGluR_(4α)receptors have been described previously (Amarori andNakanishi, Neuron 8, 757-765, 1992; Tanabe et al., Neuron 8, 169-179,1992, and J. Neurochem. 63, 2038-2047, 1993). They are maintained at 37°C. in a humidified 5% CO₂ incubator in Dubecco's Modified Eagle Medium(DMEM) containing a reduced concentration of(S)-glutamine (2 mM) and aresupplemented with 1% proline, penicillin (100 U/mL), streptomycin (100mg/mL) and 10% dialyzed fetal calf serum (all GIBCO, Paisley). Two daysbefore assay 1.8×10⁶ cells are evenly distributed into the wells of 24well plates.

[0112] Phosphatidylinositol (PI) hydrolysis can be measured as describedpreviously (Hayashi et al., Nature 366, 687-690,1992, and J.Neuroscience 14, 3370-3377, 1994). Briefly, the cells are labeled with[³H]inositol (2 μCi/mL) 24 h prior to the assay. For agonist assays, thecells are incubated with test compound dissolved in phosphate-bufferedsaline (PBS)-LiC] for 20 min, and agonist activity is determined fromthe level of ³H-labeled mono-, bis- and tris-inositol phosphatesgenerated, as measured following ion-exchange chromatography, comparedwith the level generated in the absence of the test compound. Forantagonist assays, the cells are preincubated with ligand dissolved inPBS-LiCl for 20 min prior to incubation with test compound and 10 μM(S)-Glu for 20 min. The antagonist activity is then determined as theinhibitory effect of the (S)-Glu mediated response.

[0113] The assay of cyclic AMP formation can be performed as describedpreviously (Hayashi et al., 1992, 1994). Briefly, the cells areincubated for 10 min in PBS containing test compound and 10 μM forskolinand 1 mM 3-isobutyl-1-methylxanthine (IBEM) (both Sigma, St. Louis, Mo.,USA). The agonist activity is then determined as the inhibitory effecton the forskolin-induced cyclic AMP formation. For antagonist assay, thecells are preincubated with ligand dissolved in PBS containing 1 mM IBMfor 20 min prior to a 10 min incubation in PBS containing test compound,20 μM(mGlu2) or 50 μM (mGlu4a) (S)-Glu, 10 μM forskolin and 1 mM IBMX.The antagonist activity is then determined as the potentiating effect onthe forskolin-induced cyclic AMP formation.

[0114] Some of the compounds of the invention were tested for antagonistactivity against Chinese hamster ovary cell lines expressing clonedmGluR_(1α), mGluR₂ and mGluR_(4α)at a concentration of 5 mM. Compounds4a and 4b of the invention effectively blocked the increase in PIhydrolysis by action of 10 mM (L)-glutamic acid at themGluR_(1α)receptor. The results are presented in FIG. 1.

[0115] In Vivo Testing:

[0116] In vivo testing for demonstration of the pharmacological activityof certain compounds on representative mGlu receptor subtypes can beperformed using Sprague Dawley rat tissues.

[0117] Phosphatidylinositol (PI) hydrolysis can be measured as describedbelow:

[0118] Briefly, cross-chopped slices are prepared from neonatal SpragueDawley rat tissue (age: p7-p14). The slices are pre-labelled with [3H]myo-inositol. Following pre-labelling, the slices are incubated with thetest drugs and standard (known Group I agonists i.e. ACPD) for a periodof 45 minutes. The incubation is terminated by the addition ofchloroform/methanol/HCl (100:200:2). The resulting mixture is separatedinto two phases by the addition of chloroform and distilled water. Theaqueous fraction is applied to ion exchange columns, and inositolphosphates are eluted using 800 mM Ammonium Formate/100 mM Formic Acid.The eluent is then analyzed using liquid scintillation counting. Theamount of inositol phosphate accumulation is expressed as a percentageof that induced by ACPD.

[0119] The assay of cyclic AMP formation can be performed as describedpreviously (Tovey el al., Clinica Chimica Acta, 56, 221-234, 1974). Theassay can be modelled on the cyclic AMP assay kit available fromAmersham, which in turn, is based on the assay created by Tovey el al.Briefly, samples are prepared from Sprague Dawley rat (225-250 g)cortical slices. Slices are incubated with the drug, and then challengedwith forskolin to induce cyclic AMP release. Following termination ofthe reaction by boiling, the slices are homogenized and centrifuged.Samples of supernatant are then incubated for 2-3 hours with a knownquantity of [³H]cAMP and a binding protein. When the incubation iscomplete, the bound cyclic AMP is separated from the free cyclic AMP bycentrifugation with charcoal. The resulting supernatant (containing freecyclic AMP) is then analyzed by liquid scintillation counting. Theamount of unbound cyclic AMP can be calculated from a standard curvepreviously determined with various samples of free cyclic AMP.

[0120] In performing such experiments with some of the compounds of thepresent invention, it has been demonstrated that some compounds of thepresent invention act as modulators of the cAMP-linked metabotropicglutamate receptors, while showing less activity withphosphatidylinositol-linked metabotropic glutamate receptors and viceversa.

[0121] Administration of compounds of Formula (I)

[0122] According to another aspect, the present invention provides amethod of modulating one or more mGluR functions in a warm-bloodedmammal which comprises administering an effective amount of a compoundof Formula I, or a non-toxic metabolically-labile ester or amidethereof, or a pharmaceutically acceptable salt thereof.

[0123] The compounds of the present invention are preferably formulatedprior to administration. Therefore, another aspect of the presentinvention is a pharmaceutical formulation comprising a compound ofFormula I and a pharmaceutically-acceptable carrier, diluent, orexcipient. The present pharmaceutical formulations are prepared by knownprocedures using well-known and readily available ingredients. In makingthe compositions of the present invention, the active ingredient willusually be mixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier, and may be in the form of a capsule, sachet, paper, orother container. When the carrier serves as a diluent, it may be asolid, semi-solid, or liquid material that acts as a vehicle, excipient,or medium for the active ingredient.

[0124] The compounds of Formula I are usually administered in the formof pharmaceutical compositions. These compounds can be administered by avariety of routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. These compounds areeffective as both injectable and oral compositions. Such compositionsare prepared in a manner well known in the pharmaceutical art andcomprise at least one active compound.

[0125] The present invention also provides pharmaceutical compositionscontaining compounds as disclosed in the claims in combination with oneor more pharmaceutically acceptable, inert or physiologically active,diluents or adjuvants. The compounds of the invention can befreeze-dried and, if desired, combined with other pharmaceuticallyacceptable excipients to prepare formulations for administration. Thesecompositions may be presented in any form appropriate for theadministration route envisaged. The parenteral and the intravenous routeare the preferential routes for administration.

[0126] Compounds of the general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and, if desired, other active. ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.

[0127] Compositions intended for oral use may be prepared according toany procedure known in the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate: granulating and disintegrating agents for example, cornstarch, or alginic acid: binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

[0128] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0129] Aqueous suspensions contain active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxylmethylcellulose, methyl cellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia:dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample hepta-decaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl-p-hydroxy benzoate, one or more colouringagents, one or more flavouring agents or one or more sweetening agents,such as sucrose or saccharin.

[0130] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example peanut oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavouring agents may be added to provide palatableoral preparations. These compositions may be preserved by the additionof an anti-oxidant such as ascorbic acid.

[0131] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavouring andcolouring agents, may also be present.

[0132] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oil phase may be a vegetable oil,for example olive oil or peanut oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanthnaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0133] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavouringand colouring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to known art using those suitabledispersing or wetting agents and suspending agents that have beenmentioned above. The sterile injectable preparation may also be asterile injectable solution or a suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0134] The compound(s) of the general Formula I may be administered,together or separately, in the form of suppositories for rectaladministration of the drug. These compositions can be prepared by mixingthe drug with a suitable non-irritating excipient which is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials arecocoa butter and polyethylene glycols.

[0135] Compound(s) of general Formula I may be administered, together orseparately, parenterally in sterile medium. The drug, depending on thevehicle and concentration used, can either be suspended or dissolved inthe vehicle. Advantageously, adjuvants such as local anesthetics,preservatives and buffering agents can be dissolved in the vehicle.

[0136] The dosage to be administered is not subject to defined limits,but it will usually be an effective amount. It will usually be theequivalent, on a molar basis of the pharmacologically active free formproduced from a dosage formulation upon the metabolic release of theactive free drug to achieve its desired pharmacological andphysiological effects. The compositions are preferably formulated in aunit dosage form, each dosage containing from about 0.05 to about 100mg, more usually about 1.0 to about 30 mg, of the active ingredient. Theterm “unit dosage form” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient.

[0137] The active compound is effective over a wide dosage range. Forexamples, dosages per day normally fall within the range of about 0.01to about 30 mg/kg of body weight. A typical daily dose will contain fromabout 0.01 mg/kg to about 100 mg/kg of the active compound of thisinvention. Preferably, daily doses will be about 0.05 mg/kg to about 50mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg. In thetreatment of adult humans, the range of about 0.1 to about 15 mg/kg/day,in single or divided dose, is especially preferred. However, it will beunderstood that the amount of the compound actually administered will bedetermined by a physician, in the light of the relevant circumstances,including the condition to be treated, the chosen route ofadministration, the actual compound administered, the age, weight, andresponse of the individual patient, and the severity of the patient'ssymptoms, and therefore the above dosage ranges are not intended tolimit the scope of the invention in any way. In some instances dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several smaller doses for administrationthroughout the day.

[0138] The compositions are preferably formulated in a unit dosage form,each dosage containing from about 5 mg to about 500 mg, more preferablyabout 25 mg to about 300 mg of the active ingredient. The term “unitdosage form” refers to a physically discrete unit suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical carrier, diluent, or excipient. The following formulationexamples are illustrative only and are not intended to limit the scopeof the invention in any way.

Formulation 1

[0139] Hard gelatin capsules are prepared using the followingingredients: Quantity (mg/capsule) Active Ingredient 250 Starch, dried200 Magnesium stearate  10 Total 460

Formulation 2

[0140] A tablet is prepared using the ingredients below: Quantity(mg/tablet) Active Ingredient 250 Cellulose, microcrystalline 400Silicon dioxide, fumed  10 Stearic acid  5 Total 665

Formulation 3

[0141] An aerosol solution is prepared containing the followingcomponents: Weight % Active Ingredient 0.25 Ethanol 29.75 Propellant 22(Chlorodifluoromethane) 70.00 Total 100

[0142] The active compound is mixed with ethanol and the mixture addedto a portion of the Propellant 22, cooled to −30° C. and transferred toa filling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

[0143] Tablets each containing 60 mg of active ingredient are made asfollows: Quantity (mg/tablet) Active Ingredient 60 Starch 45Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 Sodiumcarboxymethyl starch 4.5 Magnesium stearate 0.5 Talc 1.0 Total 150

[0144] The active ingredient, starch, and cellulose are passed through aNo. 45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders that are thenpassed through a No. 14 mesh U. S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

Formulation 5

[0145] Capsules each containing 80 mg medicament are made as follows:Quantity (mg/capsule) Active Ingredient 80 Starch 59 Microcrystallinecellulose 59 Magnesium stearate 2 Total 200

[0146] The active ingredient, cellulose, starch, and magnesium stearateare blended, passed through a No. 45 sieve, and filled into hard gelatincapsules in 200 mg quantities.

Formulation 6

[0147] Suppositories each containing 225 mg of active ingredient may bemade as follows: Quantity (mg/suppository) Active Ingredient  225Saturated fatty acid glycerides 2000 Total 2225

[0148] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

[0149] Suspensions each containing 50 mg of medicament per 5 mL dose aremade as follows: Active Ingredient 50 mg Sodium carboxylmethyl cellulose50 mg Syrup 1.25 mL Benzoic acid solution 0.10 mL Flavour q.v. Colorq.v. Purified water to total 5 mL

[0150] The medicament is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with someof the water and added, with stirring. Sufficient water is then added toproduce the required volume.

Formulation 8

[0151] An intravenous formulation may be prepared as follows: QuantityActive Ingredient 100 mg Mannitol 100 mg 5 N Sodium hydroxide 200 mLPurified water to total 5 mL

Formulation 9

[0152] A topical formulation may be prepared as follows: Quantity ActiveIngredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White softparaffin to 100 g

[0153] The white soft paraffin is heated until molten. The liquidparaffin and emulsifying wax are incorporated and stirred untildissolved. The active ingredient is added and stirring is continueduntil dispersed. The mixture is then cooled until solid.

Formulation 10

[0154] Sublingual or buccal tablets, each containing 10 mg of activeingredient, may be prepared as follows: Quantity (mg/tablet) ActiveIngredient 10.0 Glycerol 210.5 Water 143.0 Sodium Citrate 4.5 PolyvinylAlcohol 26.5 Polyvinylpyrrolidone 15.5 Total 410.0

[0155] The glycerol, water, sodium citrate, polyvinyl alcohol, andpolyvinylpyrrolidone are admixed together by continuous stirring andmaintaining the temperature at about 90° C. When the polymers have goneinto solution, the solution is cooled to about 50°-55° C. and themedicament is slowly admixed. The homogeneous mixture is poured intoforms made of an inert material to produce a drug-containing diffusionmatrix having a thickness of about 2-4 mm. This diffusion matrix is thencut to form individual tablets having the appropriate size.

[0156] Another preferred formulation employed in the methods of thepresent invention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts.

[0157] The construction and use of transdermal patches for the deliveryof pharmaceutical agents is well known in the art (see, for example,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991) herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

[0158] Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991, which isherein incorporated by reference.

[0159] Indirect techniques, which are generally preferred, usuallyinvolve formulating the compositions to provide for drug latentiation bythe conversion of hydrophilic drugs into lipid-soluble drugs orprodrugs. Latentiation is generally achieved through blocking of thehydroxy, carbonyl, sulfate, and primary amine groups present on the drugto render the drug more lipid soluble and amenable to transportationacross the blood-brain barrier. Alternatively, the delivery ofhydrophilic drugs may be enhanced by intra-arterial infusion ofhypertonic solutions that can transiently open the blood-brain barrier.

EXAMPLES

[0160] To gain a better understanding of the invention described herein,the following examples are set forth. It should be understood that theseexamples are for illustrative purposes only. Therefore, they should notlimit the scope of this invention in any way.

[0161] The following abbreviations are used in the Examples: EtOAc,ethyl acetate; THF, tetrahydrofuran; EtOH, ethanol; TLC, thin layerchromatography; GC, gas chromatography; HPLC, high pressure liquidchromatography; m-CPBA, m-chloroperbenzoic acid; Et₂O, diethyl ether;DMSO, dimethyl sulfoxide; DBU, 1,8-diazabicyclo-[5.4.0]undec-7-ene,MTBE, methyl t-butyl ether; and FDMS, field desorption massspectrometry.

Example 1

[0162]

[0163] Preparation of 3-carboxy-1-indanone (compound 2):

[0164] In a 3-neck round bottomed flask, fitted with a gas adapter and areflux condenser, 4.0 g of phenylsuccinic acid (1) and 4 mL of thionylchloride were refluxed for 30 min. The reaction mixture was diluted with8 mL of nitrobenzene and 4 g of aluminum chloride added in one portion.The resulting mixture was stirred at 85° C. for 1.5 h. The resultingmixture was poured into 125 mL of water and the nitrobenzene removed bysteam distillation. The product was crystallized and re-crystallizedfrom water to obtain 2.9 g (80%) of compound 2. ¹H NMR (CDCl₃) δ2.92(dd, 1H), 3.15 (dd, 1H), 4.35 (m, 1H) 4.95 (br, 1H), 7.4-7.85 (m, 4H).

[0165] Preparation of Cis- and trans-3carboxy-1indane-5,5′-hydantoin(compound 3):

[0166] 1.76 g (1.0 mmol) of the keto acid (2) was dissolved in 20 mL ofwater in a sealed tube together with 0.65 g (1.0 mmol) of potassiumcyanide and 1.92 g of ammonium carbonate (2.0 mmol). The solution wasstirred and heated to 90-100° C. for 16 h. The resulting dark solutionwas cooled and acidified with 6 N HCl and concentrated to a residuecontaining (3) which was extracted into ethanol, filtered and usedwithout further purification.

[0167] Preparation of Cis- and trans-1aminoindane-1,3-dicarbokylic acid(4a and 4b).

[0168] The residue containing compound (3) above was placed in a roundbottomed flask and refluxed together with 45 mL of 2 N NaOH for 16 h.The resulting solution was cooled, acidified with 6 N HCl and extractedinto ethanol. The ethanolic solution was treated with propylene oxide toprecipitate a mixture of crude (4a and 4b). Chromatography on Spectrum1X4 anion exchange resin with dilute acetic acid gave the separateisomers as colourless crystals, recrytalized from methanol/water.

[0169]¹H NMR (D₂O) δ2.30 (dd, 1H), 2.85 (dd, 1H), 4.05 (m, 1H), 7.2-7.4(m, 4H) for cis isomer. For trans isomer 2.70 (dd, 1H), 3.10 (dd, 1H),4.42 (m, 1H), 7.35-7.55 (m, 4H).

Example 2

[0170]

[0171] Preparation of 1-oxoindane-2-acetic acid (compound 7):

[0172] In a 3-neck flask, fitted with a pressure equalized droppingfunnel and a gas inlet adapter, 3.4 g of sodium hydride and 14.2 g ofdiethyl carbonate in 40 mL of dimethylformamide (DMF) was stirred at 65°C. A solution of 4 g of 1-indanone (5) in 10 mL DMF was added slowly andthe reaction was monitored by TLC (ethyl acetate:hexanes 2:3). Oncompletion of the reaction a solution of 7.5 g of ethylbromoacetate in20 mL DMF was added and the reaction was stirred at 65° C. foradditional 1 h. The reaction mixture was cooled and neutralized withglacial acetic acid. The solution is then evaporated to remove solventsand taken up in 50 mL of diethyl ether. The ethereal solution was washedsuccessively with water and brine, finally dried over magnesiumsulphate, filtered and evaporated to yield compound (6) as a gum.Compound (6) was used in the next reaction without further purification.Compound (2) was suspended in 25 mL of 1:1 6 N HCl:acetic acid andrefluxed for 3 h. The resulting solution was diluted with 50 mL of waterand extracted with ethyl acetate (3×20 mL). The organic layers werecombined and dried over magnesium sulphate, filtered and evaporated togive compound (7) as a gum. Flash chromatography on silica (ethylacetate:hexanes 1:1) gave pure compound (3) as a pale yellow solid. ¹HNMR (CDCl₃) δ2.60 (dd, 1H), 2.80-3.15 (m, 3H), 3.42 (dd, 1H).

[0173] Preparation of 1-indane-2-acetic acid-5,5′-hydantoin (compound8):

[0174] 1.76 g (1.0 mmol) of the keto acid (7) was dissolved in 20 mL ofwater in a sealed tube together with 0.65 g (1.0 mmol)of potassiumcyanide and 1.92 g of ammonium carbonate (2.0 mmol). The solution wasstirred and heated to 90-100° C. for 16 h. The resulting dark solutionwas cooled and acidified with 6 N HCl and concentrated to a residue ofcompound (8), that was extracted into ethanol, filtered and used withoutfurther purification.

[0175] Preparation of 1-amino-carboxyindane-2-acetic acid (compound 9):

[0176] The residue containing compound (8) as formed above was placed ina round bottomed flask and refluxed in 45 mL of 2 N NaOH for 16 h. Theresulting solution was cooled, acidified with 6 N HCl, evaporated todryness and extracted into ethanol. The ethanolic solution was treatedwith propylene oxide to precipitate a mixture of crude compound (9).Chromatography on Spectrum 1X4 anion exchange resin, with dilute aceticacid gave compound (9) as colourless crystals from methanol/water. ¹HNMR (D₂O) 2.58 (dd, 1H), 2.80-3.05 (3H), 3.42 (dd, 1H), 7.30-7.50 (2H),7.58 (m, 1H), 7.75 (d, 1H).

Example 3

[0177]

[0178] Preparation of Indan-2-one-1-acetic acid (compound 11):

[0179] A mixture of phenylglutaric acid (4.8 g, 0.023 mol) and thionylchloride (4.8 mL) in a round-bottom flask was heated to reflux for 30minutes, followed by addition of 10 mL of nitrobenzene and aluminiumchloride (4.8 g) to the mixture, respectively. The resulting mixture washeated to 80° C. for 1.5 h. The mixture was pored into water (120 mL)and nitrobenzene was removed by steam distillation. The residue waswashed with water to yield 3.9 g (90%) of compound 11 as a pale solid.

[0180] Preparation of 1-Amino-1-carboxyindane-3-acetic acid (13):

[0181] In a sealed pressure glass bottle, heated a mixture of compound11 (1.90 g, 0.010 mol), KCN (1.61 g, 0.025 mol), (NH4)₂CO₃ (6.69 g 0.070mol) and NH₄OH (1 mL) in 40 mL of water/ethanol (1:1), at 90-100 ° C.for 16 hours. The mixture was allowed to cool, acidified with 6N HCl,and concentrated in vacuo. The residue was taken up in EtOH and filteredand the filtrate was concentrated in vacuo. 45 mL of 2N NaOH was addedto the residue and t the mixture was heated to reflux for 16 hours. Themixture was allowed to cool and acidified with 6N HCl and the resultingmixture was concentrated in vacuo. The residue was taken up in EtOH andfiltered. Propylene oxide (10 mL) was added to the filtrate andresulting precipitates were filtered to obtain 1.41 g (77%) of compound13 as solid.

Example 4

[0182]

[0183] Preparation of Intermediate Compound (14):

[0184] Sodium bis(trimethylsilyl)amide (39.0 mL) was added to a stirredsolution of 1-indanone (5 g) in dry THF (123 mL) at −75° C. under N₂over 20 minutes. To the mixture was added a solution ofethylbromoacetate (4.41 mL) in dry THF (30 mL) over 25 minutes andmaintained at −75° C. for 35 minutes. (The solution turns cloudy after˜10 minutes). The mixture was warmed to −10° C. over 3 hours and 30 mLof H₂O added and the pH adjusted to about 7. The solvent was removed byrotary evaporation and the residue diluted with brine (200 mL). Thesuspension was extracted with EtOAc (4×200 mL. The EtOAc solution wasdried over MgSO₄ and concentrated to yield an oil (˜9 g). The productwas purified by column chromatography (hexanes: acetone, 9:1). Yield4.31 g (52.2%).

[0185] Preparation of Intermediate Compound (15):

[0186] Sodium bis(trimethylsilyl)amide (26.7 mL) was added to a stirredsuspension of (methoxy methyl)triphenylphosphonium chloride (9.5024 g)in dry THF (80 mL) at 0° C. under N₂. The resulting red mixture wasstirred at 0° C. for 35 minutes and a solution of 13 (4.31 g) in dry THF(40 mL) added over 10 minutes. The mixture was stirred at 0° C. for 2hours and at room temperature for 1 hour. Water (30 mL) was added andthe mixture was partitioned between brine (200 mL) and EtOAc (200 mL).The organic phase was washed with brine (2×150 mL) concentrated. Thecrude product was purified by column chromatography (hexanes: EtOAc,9:1). To obtain 3.11 g (64%) of compound 15.

[0187] Preparation of Intermediate Compound (16):

[0188] To a stirred solution of 15 and pyridine (0.429 mL) in CHCl₃ (292mL) was added trimethylsilyl iodide (3.2 mL) at 0° C., under N₂ over 7minutes. The resulting cloudy mixture was stirred at 0° C. for 1.5hours, and a further aliquot of TMSI (0.3 mL) was added. After 40 min 80mL of ice-cold 5% NaHCO₃ solution was added and the mixture stirred at0° C. for 10 minutes and partitioned between brine (500 mL) and EtOAc(800 mL). The aqueous phase was extracted with EtOAc (2×200 mL) and thecombined EtOAc extracts were washed with brine (2×200 mL). The EtOAcextracts were dried over MgSO₄ and evaporated. The crude product waspurified by column chromatography (hexanes: EtOAc, 8:1→85:15) to obtain1.89 g (63.9%) of compound 16.

[0189] Preparation of Compound (18)

[0190] A solution of compound 16 (1.89 g), KCN (1.332 g), and (NH₄)₂CO₃(5.4974 g) in EtOH (20 mL) and H₂O (20 mL) was heated in a sealedpressure tube at 85-90° C. for 18 hours. 0.65 g of KCN and 2.75 g of(NH₄)₂CO₃ was added and the reaction mixture was stirred for 2 days. Thereaction mixture was cooled and acidified with 6N HCl to pH 2 and thesolvents were removed by rotary evaporation. The residue was extractedinto EtOH and filtered, and 277 mg (13.8% from 16) of amino acid 18 wasisolated by addition of propylene oxide. Anal. Calculated for compound18: C; 62.64, H; 6.07, N; 5.62. Found: C; 61.89, H; 6.18, N; 5.51,contains 0.2 mol H₂O

[0191]¹H NMR (D₂O) δ2-2.8 (m, 3H), 3.05-3.2 (m 2H), 3.5-3.7 (dd 1H), 4.2(d 1H), 7.25 (s 4H).

Example 5

[0192]

[0193] Preparation of Intermediate Compound (2):

[0194] A suspension of compound 1 (4 g) in SOCl₂ (5 mL) was refluxedwith stirring for 35 minutes. Nitrobenzene (20 mL) and anhydrous AlCl₃(4 g) were added and the mixture stirred at 80° C. for 1 hour and 45minutes, the mixture was poured into water (125 mL) and most of thesolvent removed by rotary evaporation. The residue was suspend in water(300 mL), extracted with EtOAc (3×200 mL). The combined EtOAc extractswere washed with brine, dried and concentrated. The product was purifiedby column chromatography (hexanes:EtOAc:HCO₂H, 6:4:0.1) to obtain 2.91 gof compound 2 as pale brown solid.

[0195] Preparation of Intermediate Compound (19):

[0196] DCC (1.47 g) was added to a stirred solution of compound 2 (1.045g) in MeOH (dry, 1.3 equivalents) and dry CH₂Cl₂ (50 mL), followed by 5mg of DMAP. The mixture was stirred overnight and the resultingsuspension filtered through paper. The solvent was removed by rotaryevaporation and the residue was purified by column chromatography(hexanes:EtOAc, 75:25) to obtain 0.849 g of compound 19 as pale brownsolid.

[0197] Preparation of Intermediate Compound (20):

[0198] 1 M of NaN₃(TMS)₂ (31.73 mL) in THF was added to a stirredsuspension of Ph₃PCH₂OCH₃Cl (11.25 g) in dry THF (90 mL) at 0° C. underN₂. After 55 minutes a solution of compound 19 (4.2864 g) in THF wasadded over 25 minutes. The mixture was stirred at 0° C. for 2 hours andat room temperature overnight. The mixture was diluted with 500 mL ofwater and extracted with EtOAc (4×150 mL), the organic extracts werewashed with brine, dried and concentrated. The crude product waspurified by column chromatography (hexanes:EtOAc, 9:1) to obtain 1.617 gof compound 20 as a clear oil.

[0199] Preparation of Intermediate Compound (21):

[0200] TMSI (1.56 mL) was added to a stirred solution of compound 20(1.4367 g) and pyridine (0.21 mL) in dry CHCl₃ (140 mL) under N₂ at 0°C. the mixture was stirred at 0° C. for 1.5 hours and more TMSI (0.8 mL)was added. After stirring at 0° C. for 0.5 hours, and then at roomtemperature for 2 h, the mixture was cooled again to 0° C. and 5% NaHCO₃added to quench the reaction. The resulting mixture was diluted withEtOAc, washed with brine once, diluted Na₂S₂O₃ solution, brine (twice),dried and concentrated. The product was purified. with columnchromatography (hexanes:EtOAc, 8:2) to obtain 0.68 g of compound 21 as afaint yellow oil.

[0201] Preparation of Intermediate Compound (23):

[0202] A mixture of compound 21 (0.65 g), KCN (0.54 g) and (NH₄)₂CO₃(2.2319 g) in a solution of EtOH/H₂O (8 mL/8 mL) was stirred in apressure tube at −100° C. for 3 days. More KCN (0.27 g) and (NH₄)₂CO₃(1.11 g) were added to the mixture after 27 hours. The mixture wascooled down to room temperate and acidified with 6 N HCl to pH˜2, andthe solvents removed by rotary evaporation. MeOH was added to theresidue and the resulting suspension was filtered. The filtrate wasconcentrated and the resulting residue was dissolved in 3 N NaOH (40 mL)and refluxed for 2 days. The obtained crude product was re-dissolved in2 N NaOH/1,4-dioxane (13 mL:13 mL) and CbzCl (0.67 mL) was added at 0°C., while stirring. The mixture was stirred for 1 hour at 0° C. and atroom temperature for 2 days. More CbzCl was added to the reactionmixture (0.9 mL after 7 hours, 0.5 mL after 1 day) and 2 N NaOH added toadjust the pH to ˜9.

[0203] The mixture was extracted with EtOAc (4×50 mL). The aqueoussolution was cooled to 0° C., acidified with 6 N HCl to pH ˜2 andextracted with EtOAc (4×150 mL). Combined organic extracts were washedwith brine (2×100 mL), dried and concentrated. The crude product waspurified by column chromatography (CH₂Cl₂: Acetone:HCO₂H, 85:15:1) toobtain protected form of compound 23. This product was hydrogenized in20 mL MeOH with 10% Pd/C (18 mg) under H₂ for 24 hours. The solution wasfiltered through Celite and crystallized from MeOH to obtain 82.4 mg ofcompound 23 as an off-white solid. Elemental analysis calc. for compound23: C; 60.12, H; 5.68, N; 5.84. Found: C; 60.11, H; 5.55, N; 5.79. ¹HNMR (D₂O) δ2.2 (t, 2H), 3.6-3.8 (m, 2H due to overlapping singleprotons), 3.9 (d, 1H), 7.3 (s, 4H).

Example 6

[0204] In Vivo Testing of Exemplary Compounds:

[0205] Cyclic AMP Assay:

[0206] Rationale:

[0207] Group II/III metabotropic glutamate receptors (mGluRs) arenegatively coupled to adenylate cyclase, and agonists of these receptorslead to a decrease in intracellular cyclic AMP accumulation.

[0208] Method:

[0209] The assay has been modeled on the cyclic AMP assay kit availablefrom Amersham. This kit, in turn, is based on the assay created by Toveyet al. (1974). Briefly, the samples were prepared from Sprague Dawleyrat (225-250 g) cortical slices. Slices were incubated with the testcompound (drug), and then challenged with forskolin to induce cyclic AMPrelease. Following termination of the reaction by boiling, the sliceswere homogenized and centrifuged. Samples of supernatant were thenincubated for 2-3 hours with a known quantity of [³H]cAMP and a bindingprotein. When the incubation was complete, the bound cyclic AMP wasseparated from the free cyclic AMP by centrifugation with charcoal. Theresulting supernatant (containing free cyclic AMP) was then analyzed byliquid scintillation counting. The amount of unbound cyclic AMP wascalculated from a standard curve previously determined with varioussamples of free cyclic AMP.

[0210] Results Interpretation:

[0211] If the drugs tested inhibit forskolin-induced cyclic AMPaccumulation, they are considered to be Group II/III agonists.Conversely, if they inhibit the decrease in forskolin-induced cyclic AMPaccumulation caused by glutamate, they are considered to be Group II/IIIantagonists.

[0212] Results: Group II/III Group II/III Aminoindane Agonist EC₅₀ (M)Antagonist EC₅₀ (M) Trans-1- No — No — aminoaindane- 1,3-dicarboxylicacid Compound 4a Cis-1-aminoindane- Yes 2.1 × 10⁻⁶ No — 1,3-dicarboxylicacid Compound 4b Trans-1-amino-1- No — Yes 3.4 × 10⁻⁸ carboxyindane-2-acetic acid Compound 9 Trans-1-amino-1- Yes 9.9 × 10⁻⁷ No —carboxyindane-3- acetic acid Compound 13 1-[2-amino]-2- Yes 4.6 × 10⁻⁷Yes 2.6 × 10⁻⁸ indanediacetic acid Compound 18 1-[2-amino]-3- No — Yes6.1 × 10⁻⁷ carboxyindaneacetic acid Compound 23

[0213] Phosphatidylinositol Assay

[0214] Rationale:

[0215] Group I metabotropic glutamate receptors (mGluRs) are positivelycoupled on inositol phosphate metabolism. Agonists at these receptorslead to an increase in intracellular free inositol phosphates, whileantagonists inhibit the increase in intracellular free inositolphosphate induced by standard agonists (i.e. ACPD).

[0216] Method:

[0217] Cross-chopped slices were prepared from neonatal Sprague Dawleyrat tissue (age: p7-p14). The slices were pre-labelled with [³H]myo-inositol. Following pre-labelling, the slices were incubated withthe test compounds and standard (known Group I agonists i.e. ACPD) for aperiod of 45 minutes. The incubation was terminated by the addition ofchloroform/methanol/HCl (100:200:2). The resulting mixture was separatedinto two phases by the addition of chloroform and distilled water. Theaqueous fraction was applied to ion exchange columns, and inositolphosphates were eluted using 800 mM Ammonium Formate/100 mM Formic Acid.The eluent was then analyzed using liquid scintillation counting. Theamount of inositol phosphate accumulation was expressed as a percentageof that induced by ACPD.

[0218] Results Interpretation:

[0219] If the drugs cause an increase in intracellular free inositolphosphate accumulation, they are considered to be Group I agonists. Ifthey inhibit the increase in intracellular free inositol phosphateaccumulation induced by ACPD, they are considered to be Group IIantagonists.

[0220] Results: Group I Group I Aminoindane Agonist EC₅₀ (M) AntagonistEC₅₀ (M) Trans-1-aminoaindane- No — Yes 4.8 × 10⁻⁷ 1,3-dicarboxylic acidCompound 4a Cis-1-aminoindane- No — No — 1,3-dicarboxylic acid Compound4b Trans-1-amino-1- No — Yes 1.1 × 10⁻⁶ carboxyindane-2-acetic acidCompound 9 Trans-1-amino-1- No — Yes 1.3 × 10⁻⁹ carboxyindane-3-aceticacid Compound 13 1-[2-amino]-2- No — Yes 1.4 × 10⁻⁵ indanediacetic acidCompound 18 1-[2-amino]-3- No — No — carboxyindaneacetic acid Compound23

[0221] The invention being thus described, it will be obvious that thesame may be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the invention, and all suchmodifications as would be obvious to one skilled in the art are intendedto be included within the scope of the following claims.

What is claimed is:
 1. A compound having structural formula (I):

stereoisomers thereof, or pharmaceutically acceptable salts or hydratesthereof, wherein: R1, and R2 are selected from the group comprising: i)H ii) an acidic group selected from the group comprising carboxy,phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol,—(CH₂)_(n)-carboxy, —(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino,—(CH₂)_(n)-sulfono, —(CH₂)_(n)-sulfino, —(CH₂)_(n)-borono,—(CH₂)_(n)-tetrazol and —(CH₂)_(n)-isoxazol, where n=1, 2, 3, 4, 5, or6; X is an acidic group selected from the group comprising carboxy,phosphono, phosphino, sulfono, sulfino, borono, tetrazol and isoxazol; Yis a basic group selected from the group comprising 1° amino, 2° amino,3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2°amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternaryammonium salts, imidazol, guanidino, boronoamino, allyl, urea andthiourea; m is 0, 1; and R3, R4, R5, R6 are independently H, nitro,amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo,carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester orsalt thereof; with the proviso: i) when X is COOH, Y is NH₂,R3=R4=R5=R6=H, then both R1 and R2 are not H at the same time; ii) whenn=0, X is COOH, Y is NH₂, R1=R2=R6=H and one of the groups R3, R4 or 5is COOH, then the remaining two groups of R3, R4 and R5 are not both Hat the same time.
 2. The compound according to claim 1, wherein R1 is H,CO₂H or CH₂CO₂H.
 3. The compound according to claim 1, wherein R2 is H,CO₂H, or CH₂CO₂H.
 4. The compound according to claim 1, wherein saidcompound is selected from the group of compounds:


5. A process for the preparation of a compound of Formula I:

or a pharmaceutically acceptable metabolically-labile ester or amidethereof, or a pharmaceutically acceptable salt thereof, wherein: R1, andR2 are selected from the group comprising: i) H ii) an acidic groupselected from the group comprising carboxy, phosphono, phosphino,sulfono, sulfino, borono, tetrazol, isoxazol, —(CH₂)_(n)-carboxy,—(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino, —(CH₂)_(n)-sulfono,—(CH₂)_(n)-sulfino, —(CH₂)_(n)-borono, —(CH₂)_(n)-tetrazol and—CH₂)_(n)-isoxazol, where n=1, 2, 3, 4, 5, or 6; X is an acidic groupselected from the group comprising carboxy, phosphono, phosphino,sulfono, sulfino, borono, tetrazol and isoxazol; Y is a basic groupselected from the group comprising 1° amino, 2° amino, 3° amino,quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino,aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1°amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternaryammonium salts, imidazol, guanidino, boronoamino, allyl, urea andthiourea; m is 0, 1; and R3, R4, R5, R6 are independently H, nitro,amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo,carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester orsalt thereof; which comprises: b) hydrolyzing a compound of formula(IIa) or (IIb):

wherein: R1, and R2 are selected from the group comprising: i) H ii) anacidic group selected from the group comprising carboxy, phosphono,phosphino, sulfono, sulfino, borono, tetrazol, isoxazol,—(CH₂)_(n)-carboxy, —(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino,—(CH₂)_(n)-sulfono, —(CH₂)_(n)-sulfino, —(CH₂)_(n)borono,—CH₂)_(n)-tetrazol and —(CH₂)_(n)-isoxazol, wherein n=1, 2, 3, 4, 5, or6; and R3, R4, R5 and R6 are independently H, nitro, amino, halogen,tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl,sulfamoyl, or pharmaceutically acceptable ester or salt thereof, R7 is ahydrogen atom or an acyl group. Preferred functional groups for R7 arehydrogen and C₂-C₆ alkanoyl groups, such as acetyl; or c) hydrolyzing acompound of formula (IIa) or (IIIb):

wherein: R1, R2, R3, R4, R5 and R6 are as defined above, R8 and R9 areeach independently represent a hydrogen atom, a (C₂-C₆) alkanoyl group,a (C₁-C₄) alkyl group, a (C₃-C₄) alkenyl group or a phenyl (C₁-C₄) alkylgroup wherein the phenyl is unsubstituted or substituted by halogen,(C₁-C₄) alkyl or (C₁-C₄) alkoxy, or a salt thereof, or d) deprotecting acompound of formula (IVa) or (IVb)

wherein: R1, R2, R3, R4, R5 and R6 are as defined above and R10 is ahydrogen atom or a carboxyl protecting group, or a salt thereof, and R11represents a hydrogen atom or a nitrogen protecting group; whereafter,if necessary and/or desired, the following steps are carried out: (i)resolving the compound of Formula I; (ii) converting the compound ofFormula I into a non-toxic metabolically labile ester or amide thereofand/or; (iii) converting the compound of Formula I or a non-toxicmetabolically labile ester or amide thereof into a pharmaceuticallyacceptable salt thereof.
 6. A pharmaceutical composition comprising apharmaceutically acceptable carrier, diluent or excipient, and acompound of structural formula (I):

or stereoisomers thereof, or pharmaceutically acceptable salts orhydrates thereof, wherein: R1, and R2 are selected from the groupcomprising: i) H ii) an acidic group selected from the group comprisingcarboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol,isoxazol, —(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino,—(CH₂)_(n)-sulfono, —(CH₂)_(n)-sulfino, —(CH₂)_(n)-borono,—(CH₂)_(n)-tetrazol, and —(CH₂)_(n)-isoxazol, where n=1, 2, 3, 4, 5, or6; X is an acidic group selected from the group comprising carboxy,phosphono, phosphino, sulfono, sulfino, borono, tetrazol, and isoxazol;Y is a basic group selected from the group comprising 1° amino, 2°amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino,aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammoniumsalts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromaticquaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, ureaand thiourea; m is 0, 1; and R3, R4, R5, R6 are independently H, nitro,amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo,carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester orsalt thereof.
 7. The pharmaceutical composition of claim 6, wherein saidcompound is selected from the group of compounds:


8. A use of an effective amount of a compound of structural formula (I):

or stereoisomers thereof, or pharmaceutically acceptable salts orhydrates thereof, in modulating one or more metabotropic glutamatereceptor functions in warm blooded mammals, wherein said use comprisesadministering an effective amount of a compound of formula (I); wherein:R1 and R2 are selected from the group comprising: i) H ii) an acidicgroup selected from the group comprising carboxy, phosphono, phosphino,sulfono, sulfino, borono, tetrazol, isoxazol, —(CH₂)_(n)-carboxy,—(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino, —(CH₂)_(n)-sulfono,—(CH₂)_(n)-sulfino, —(CH₂)_(n)-borono, —(CH₂)_(n)-tetrazol, and—(CH₂)_(n)-isoxazol, where n=l, 2, 3, 4, 5, or 6; X is an acidic groupselected from the group comprising carboxy, phosphono, phosphino,sulfono, sulfino, borono, tetrazol and isoxazol; Y is a basic groupselected from the group comprising 1° amino, 2° amino, 3° amino,quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino,aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1°amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternaryammonium salts, imidazol, guanidino, boronoamino, allyl, urea andthiourea; m is 0, 1; and R3, R4, R5, R6 are independently H, nitro,amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo,carboxy, carbamoyl, sulfamoyl and pharmaceutically acceptable ester orsalt thereof,
 9. A use of an effective amount of a compound ofstructural formula (I):

or stereoisomers thereof, or pharmaceutically acceptable salts orhydrates thereof, in treating a neurological disease or disorderselected from the group comprising: cerebral deficits subsequent tocardiac bypass surgery and grafting, cerebral ischemia, stroke, cardiacarrest, spinal cord trauma, head trauma, perinatal hypoxia, andhypoglycemic neuronal damage, Alzheimer's disease, Huntington's Chorea,amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage,retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms, convulsions, migraine headaches,urinary incontinence, psychosis, drug tolerance, withdrawal andcessation (i.e. opiates, benzodiazepines, nicotine, cocaine, orethanol), smoking cessation, anxiety and related disorders (e.g. panicattach), emesis, brain edema, chronic pain, sleep disorders, Tourette'ssyndrome, attention deficit disorder, and tardive dyskinesia, whereinsaid use comprises administering an effective amount of a compound offormula (I); wherein: R1, and R2 are selected from the group comprising:i) H ii) an acidic group selected from the group comprising carboxy,phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol,—(CH₂)_(n)-carboxy, —(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino,—(CH₂)_(n)-sulfono, —(CH₂)_(n)-sulfino, —(CH₂)_(n)-borono,—(CH₂)_(n)-tetrazol, and —(CH₂)_(n)-isoxazol, where n=1, 2, 3, 4, 5, or6; X is an acidic group selected from the group comprising carboxy,phosphono, phosphino, sulfono, sulfino, borono, tetrazol and isoxazol; Yis a basic group selected from the group comprising 1° amino, 2° amino,3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2°amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternaryammonium salts, imidazol, guanidino, boronoamino, allyl, urea andthiourea; m is 0, 1; and R3, R4, R5, R6 are independently H, nitro,amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo,carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester orsalt thereof.
 10. A use of an effective amount of a compound ofstructural formula (I):

or stereoisomers thereof, or pharmaceutically acceptable salts orhydrates thereof, in treating a psychiatric disease or disorder selectedfrom the group comprising: schizophrenia, anxiety and related disorders(e.g. panic attack), depression, bipolar disorders, psychosis, andobsessive compulsive disorders, wherein said use comprises administeringan effective amount of a compound of formula (I); wherein: R1, and R2are selected from the group comprising: i) H ii) an acidic groupselected from the group comprising carboxy, phosphono, phosphino,sulfono, sulfino, borono, tetrazol, isoxazol, —(CH₂)_(n)-carboxy,—(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino, —(CH₂)_(n)-sulfono,—(CH₂)_(n)-sulfino, —(CH₂)_(n)-borono, —(CH₂)_(n)-tetrazol and—CH₂)_(n)-isoxazol, where n-1, 2, 3, 4, 5, or 6; X is an acidic groupselected from the group comprising carboxy, phosphono, phosphino,sulfono, sulfino, borono, tetrazol and isoxazol; Y is a basic groupselected from the group comprising 1° amino, 2° amino, 3° amino,quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino,aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1°amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternaryammonium salts, imidazol, guanidino, boronoamino, allyl, urea andthiourea; m is 0, 1; and R3, R4, R5, R6 are independently H, nitro,amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo,carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester orsalt thereof.
 11. The use according to any one of claims 8, 9 and 10wherein said compound is selected from the group of compoundscomprising:


12. A compound of formula (IIa):

wherein: R1, and R2 are selected from the group consisting of: i) H; ii)an acidic group selected from the group comprising carboxy, phosphono,phosphino, sulfono, sulfino, borono, tetrazol, isoxazol,—(CH₂)_(n)-carboxy, —(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino,—(CH₂)_(n)-sulfono, —(CH₂)_(n)-sulfino, —(CH₂)_(n)-borono,—(CH₂)_(n)-tetrazol and —(CH₂)_(n)-isoxazol, where n=1, 2, 3, 4, 5, or6; R3, R4, R5 and R6 are independently H, nitro, amino, halogen,tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl,sulfamoyl, or pharmaceutically acceptable ester or salt thereof, R7 is ahydrogen atom or an acyl group. Preferred functional groups for R7 arehydrogen and (C₂-C₆) alkanoyl groups, such as acetyl.
 13. A compound offormula (IIIa):

wherein: wherein: R1 and R2 are selected from the group consisting of:i) H; ii) an acidic group selected from the group comprising carboxy,phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol,—(CH₂)_(n)-carboxy, —(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino,—(CH₂)_(n)-sulfono, —(CH₂)_(n)-sulfino, —(CH₂)_(n)-borono,—(CH₂)_(n)-tetrazol and —(CH₂)_(n)-isoxazol, where n=1, 2, 3, 4, 5, or6; R3, R4, R5 and R6 are independently H, nitro, amino, halogen,tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl,sulfamoyl, or pharmaceutically acceptable ester or salt thereof; R8 andR9 are each independently represent a hydrogen atom, a (C₂-C₆) alkanoylgroup, a (C₁-C₄) alkyl group, a (C₃-C₄) alkenyl group or a phenyl(C₁-C₄) alkyl group wherein the phenyl is unsubstituted or substitutedby halogen, (C₁-C₄) alkyl or (C₁-C₄) alkoxy, or a salt thereof.
 14. Acompound of formula (IVa):

wherein: wherein: wherein: R1, and R2 are selected from the groupconsisting of: i) H iii) an acidic group selected from the groupcomprising carboxy, phosphono, phosphino, sulfono, sulfino, borono,tetrazol, isoxazol, —(CH₂)_(n)-carboxy, (CH₂)_(n)-phosphono,—(CH₂)_(n)-phosphino, —(CH₂)_(n)-sulfono, —(CH₂)_(n)-sulfino,—(CH₂)_(n)-borono, —(CH₂)_(n)-tetrazol and —(CH₂)_(n)-isoxazol, wheren=1, 2, 3, 4, 5, or 6; R3, R4, R5 and R6 are independently H, nitro,amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo,carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester orsalt thereof; R10 is a hydrogen atom or a carboxyl protecting group, ora salt thereof, and R11 is a hydrogen atom or a nitrogen protectinggroup; with the proviso, when R1=R2=R3=R4=R5=R6=H and: i) R11 is H thenR10 is other than methyl or ethyl; or ii) R11is —CO₂CH₂C₆H₅ then R10 isother than H or CH₃.
 15. A compound of formula (IIb):

wherein: wherein: wherein: R1 and R2 are selected from the groupconsisting of: i) H iv) an acidic group selected from the groupcomprising carboxy, phosphono, phosphino, sulfono, sulfino, borono,tetrazol, isoxazol, —(CH₂)_(n)-carboxy, —(CH₂)_(n)-phosphono,—(CH₂)_(n)-phosphino, —(CH₂)_(n)-sulfono, —(CH₂)_(n)-sulfino,—(CH₂)_(n)-borono, —(CH₂)_(n)-tetrazol and —(CH₂)_(n)-isoxazol, wheren=1, 2, 3, 4, 5, or 6; R3, R4, R5 and R6 are independently H, nitro,amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo,carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester orsalt thereof; R7 is a hydrogen atom or an acyl group. Preferredfunctional groups for R7 are hydrogen and (C₂-C₆) alkanoyl groups, suchas acetyl.
 16. A compound of formula (IIIb):

wherein: R1, and R2 are selected from the group consisting of: i) H ii)an acidic group selected from the group comprising carboxy, phosphono,phosphino, sulfono, sulfino, borono, tetrazol, isoxazol,—(CH₂)_(n)-carboxy, —(CH₂)_(n)-phosphono, —(CH₂)_(n)-phosphino,—(CH₂)_(n)-sulfono, —(CH₂)_(n)-sulfino, —(CH₂)_(n)-borono,—(CH₂)_(n)-tetrazol and —(CH₂)_(n)-isoxazol, where n=1, 2, 3, 4, 5, or6; R3, R4, R5 and R6 are independently H, nitro, amino, halogen,tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl,sulfamoyl, or pharmaceutically acceptable ester or salt thereof; R8 andR9 are each independently represent a hydrogen atom, a (C₂-C₆) alkanoylgroup, a (C₁-C₄) alkyl group, a (C₃-C₄) alkenyl group or a phenyl(C₁-C₄) alkyl group wherein the phenyl is unsubstituted or substitutedby halogen, (C₁-C₄) alkyl or (C₁-C₄) alkoxy, or a salt thereof.
 17. Acompound of formula (IVb):

wherein: wherein: wherein: R1 and R2 are selected from the groupconsisting of: i) H ii) an acidic group selected from the groupcomprising carboxy, phosphono, phosphino, sulfono, sulfino, borono,tetrazol, isoxazol, —(CH2)_(n)-carboxy, —(CH₂)_(n)-phosphono,—(CH₂)_(n)-phosphino, —(CH₂)_(n)-sulfono, —(CH₂)_(n)-sulfino,—(CH₂)_(n)-borono, —(CH₂)_(n)-tetrazol and —(CH2)_(n)-isoxazol, wheren=1, 2, 3, 4, 5, or 6; R3, R4, R5 and R6 are independently H, nitro,amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo,carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester orsalt thereof; R10 is a hydrogen atom or a carboxyl protecting group or asalt thereof, and R11 is a hydrogen atom or a nitrogen protecting group;with the proviso, when R1=R2=R3=R4=R5=R6=R10=H, then R11 is other thanCO₂t-Bu.